throbber
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`
`Canadian
`Intellectual Property
`Office
`
`Office de la Propriete
`lntellectuelle
`du Canada
`
`(11) CA623411
`
`(13JA
`
`(40)
`
`04.07.1961
`
`An Agency of
`Industry Canada
`
`Un organisme
`d'industrie Canada
`
`(12)
`
`(21) Application number: 623411 D
`(22) Date of filing:
`
`(51) Int. Cl:
`
`(71) Applicant:
`
`HAUSMANN LAB LTD.
`
`(72) Inventor:
`
`MULLER ARTHUR().
`BERSIN THEODOR().
`
`(54) PROCESS FOR THE MANUFACTURE OF IRON-
`POL YISOMAL TOSE COMPLEX FOR THERAPEUTICAL
`PURPOSES
`
`(57) Abstract:
`
`This First Page has been artificially created and is not part of the CIPO Official Publication
`
`Pharmacosmos, Exh. 1032, p. 1
`
`

`

`6234Ij
`
`-2-
`
`This invention relates to a process tor the
`preparation ot j.ron-poly1somaltose
`tor parenteral injection.
`
`complexes suitable
`
`It is known that a colloidal j.ron dextran
`complex can be prepared by dissolving, with heating it
`necessary, a suitable water-soluble dextran ot a
`particular intrinsic viscosity, i.e. a dextran (polyisomaltose)
`having a molecular weight within a particular range, 1n
`a solution or suspension ot an iron salt, adding an excess
`ot alkali, or by dissolving the dextran in an alkali
`and then adding the j.ron compound in solution or suspension.
`The partly depolymerized dextran used in the manufacture
`ot these iron dextran complexes is obtained by hydrolyzing
`crude dextran in the usual manner, tor example with dilute
`mineral acid, and precipitating and isolating from the
`aqueous solution, the desj.red dext:Oan residue with the help
`ot water-miscible organic liquids, such as alcohols or
`ketones. Res~dues of this nature with intrinsic viscosities
`ot 0•025 to 0.25 at 25°c. have been described as usetul
`starting material.
`(See Canadian Patent 556,877, London et al,·.·
`May 6, 1958, the disclosure ot which is hereby 1nco~porated
`into the present application by reference.)
`+his
`In contrast to iihe two-stage process 1n which
`dextran ot a particular 1ntr1nsic viscosity must be
`employed, the present invention makes it possible to use
`
`crude dextran ot ~ particle size, preferably one having
`an intrinsic viscosity ot between 0.25 to 0.75 at 25°c.
`
`· ·
`
`10
`
`20
`
`:··:·.
`
`Pharmacosmos, Exh. 1032, p. 2
`
`

`

`- 3 -
`
`623411
`
`This is done according to the process of the
`
`present invention in a single stage by heating the
`
`solution or suspension of the crude dextran together
`
`with an, acidic solution of a ferric (iron III) salt until
`
`the intrinsic viscosity at 25°0. is at the most O.l, and
`
`subsequently ~reating the mixture with an alkali and then
`
`isolating and purifying the resulting ferric complex by
`
`known means.
`
`10
`
`invention there can be added to the acid-reacting solution
`
`In a pref erred procedure according to the
`
`of the iron salt to inhibit hydrolysis, an acid with the
`
`same anion. It is also of advantage to make the solution
`
`of the iron-polyisomaltose complex isotonic by dialysis
`
`against water or by ion exchange. For the preparation of
`
`a solid iron-polyisomaltose complex according to prefer(cid:173)
`
`red aspects of the invention, the solution of the iron(cid:173)
`
`polyisomal tose is concentrated in vacuum, or the complex
`
`precipitated, isolated a.nl: ·dried by the addition of a
`
`suitable water-miscible solvent. The alkaline solution
`
`20
`
`of the iron-polyisomaltose complex oan be neutralized
`
`before purification and isolation by addition of a solid,
`
`liquid or gaseous acid, for example, an ion-exchanger,
`
`sulfuric acid or hydrochloric acid.
`
`~he preparation of the iron-polyisomal.tose complex
`
`according to the invention does away with the time-consuming,
`
`technical.J.y difficul~ and low-yield preparation of exactly
`
`defined, low polymer homologs of dextran for use as
`
`starting material. It makes possible the preparation in
`
`a single-stage of iron-polyisomaltose complexes suitable
`
`30
`
`for therapeutic application from higher molecular weight
`
`,;
`
`:.1··
`
`'_-; ..
`
`Pharmacosmos, Exh. 1032, p. 3
`
`

`

`62341,
`
`-4-
`
`In contrast to
`dextrans or their homologous polymers.
`the usual two-stage process, the one-stage process ot
`. the invention provides an iron-polyisomaltose complex
`which is more heterogenous in particle size, but surprisingly
`ot lower toxicity, better pharmacological properties,
`compatible and ot higher therapeutic ett1caoy than the
`1ron-dextran complexes hitherto known.
`A preparation made according to the invention
`provided the following results in an acute tox1e1ty test
`on rabbits. At a dose ot 690 mg Fe/kg intramuscular, all
`animals survived. With the same dose and the same method
`ot application ot a ·cOJD11ercial preparation, two-thirds ot
`the animals died within eight weeks.
`Intramuscular
`application into young pigs a tew days atter birth, ot
`prior preparations ot ~ron-dextran in a dosage ot 100 mg
`Pe/animal, caused either the death' of all animals
`(B. Jaebrens, Mh. Veterinlrm.ed. ,g.422, 1957 ), or led atter
`tour weeks to a med1um gain in weight ot only -t0.81 kg
`com.pared with the controls (M.I.SWenson et al., J. Am.Vet.
`.
`.
`Med. Assoc. 131 1 146, 1957). on the other hand, the iron-
`polyisomaltose ot the invention led with the same arrange(cid:173)
`ment of tests to an average gain in weight of -t- 2.55 kg.
`The"1ron-poly1somaltoee" of the invention is
`.
`a complex compound consisting of iron hydroxide and poly-
`isomaltose, a polyhexosan.
`In analogy to the nomenclature
`in Chemical Abstracts' (e.g. polyhexosan ~ glucosan ---)'
`dextran ~ poly1som.altose) the COlllPound could be designated
`"poly1somaltose 1ron~(III) bydrox1de 11
`• While "poly1so(cid:173)
`~altosen is a term used.loosely tor 11dextran", .the latter
`.
`.
`is a compound• ot very h1gh molecular weight, whereas
`
`,
`
`10
`
`20
`
`Pharmacosmos, Exh. 1032, p. 4
`
`

`

`- 5 -
`
`62341.
`
`polyisomaltose is a degradation product of dextran.
`
`Moreover the polyisomaltose in the appLicants' complex
`
`lacks the disadvantages of certain clinical dextrans.
`
`The process according to the invention is
`
`explained in more detail by the following examples:
`
`EX.AMPLE I
`
`50 g dextran (intrinsic viscosity 0.34) were
`dissolved in water to make 420 cm3. 80 cm3 of 30% by
`
`10
`
`weight FeCl.3.6 H20 were added, and the solution, being
`0.206 molar-solution in regard to Fec13 , was boiled with
`refl.ux until the relative viscosity of a reaction solution,
`
`diluted to 2% dextran, was l..095 - 1.105. The acidic
`turbid liquid was cooled, poured while stirring to 50 cm3
`of 15-N caustic soda, heated for 20 minutes in a boiling
`
`water bath, whereupon the cool.ed reaction mixture was
`
`separated from undissolved particles by centrifuging. The
`
`alkaline solution was neutralized with hydrochloric acid,
`
`precipitated with isopropanol in the proportion of 1.1 parts
`aqueous solution +. 1.5 parts al.cohol, and the mixture stored
`
`20
`
`for 20 minutes in the refrigerator. The supernatant solution
`
`was decanted, the iron complex deposit dissolved in water
`
`to make the original vol.ume of the neutraJ.ized solution and
`
`the precipitation repeated with isopropanol in the proportion
`
`of 1.1 parts solution • 1.3 parts alcohol. The deposit
`
`was dried in vacuo after decanting, or ground in a mortar
`
`with isopropanol, drawn off by suoti.on, washed with a
`
`iittle ether, and dried in vacuo. The substance was made
`
`into an aqueous, sterile, blood-isotonic solution contain(cid:173)
`
`ing 5% tri.valent iron.
`
`Pharmacosmos, Exh. 1032, p. 5
`
`

`

`- 6 -
`
`EXAMPLE II
`
`50 g dextran (intrinsic viscosity 0.30) were
`
`boiled with reflux with 412 cm3 water, 80 cm3 30-weight
`% Fec13 .6 H20 - solution and 8.32 cm3 37% hydrochloric
`acid, until the relative viscosity of a reaction solution
`
`diluted to 2% polyisomaltose was 1.095 - 1.105. The
`
`cooled. clear solution was added under constant stirring
`
`to 50 cm3 caustic soda of about 15-N. heated for 20 minutes
`
`in a boiling water bath and the cooled reaction mixture
`
`10
`
`was centrifuged. The alkaline solution was dialyzed
`
`against ion-free water, the dialyzed solution concentrated
`
`by means of vacuum distillation and sterilized after
`
`adjusting to an iron content of 5% and being rendered
`
`isotonic.
`
`EXAMPLE III
`
`To the alkaline reaction mixture prepared
`
`according to Example II, there was added a mixture of
`
`68 om3 of wet, strongly alkaline anion exchanger in the
`
`OH form, and 60 cm3 wet, strongly acid cation exchanger in
`
`20
`
`the H form, shaken for a short time. the neutralized
`
`solution (pH 6.9) filtered off and concentrated by vacuum
`
`distillation until it contained 5% iron.
`
`Pharmacosmos, Exh. 1032, p. 6
`
`

`

`The embodiments of the invention in which an
`exclusive property or privilege is claimed are defined
`as follows.
`
`l.
`
`A process for the manufacture of therapeutically
`
`useful iron-polyisomaltose complexes, comprising heating
`
`in a single stage a solution or suspension of crude dex~ran
`of intrinsic viscosity at 25°c. of between 0.25 and 0.75
`with an acidic solution of a ferric salt until the intrinsic
`viscosity at 25°0. is at the most 0.1, subsequently treating
`
`the mixture with alkali, and isolating and purifying the
`
`iron-polyisomaltose formed.
`
`2.
`
`A process as defined in claim 1, in which an
`
`acid of the same anion as that.of the iron salt is added
`
`to inhibit hydrolysis of the acidic iron salt.
`
`A process as defined in claim 1 in which the
`
`solution of iron-polyisoma1tose complex is rendered
`
`isotonic.
`
`A process as defined in claim l, 2 or 3 in which
`
`an iron-polyisomal.tose is formed by concentrating the iron(cid:173)
`
`polyisomaltose solution by distillation in vacuum.
`
`A process as defined in claim l, 2 or 3, in which
`
`5.
`a solid iron-polyiaomaltose complex is formed by
`
`precipitating the complex from solution by the addition of
`
`a suitable water miscible solvent, and the precipitate
`
`isolated and dried.
`
`A therapeutically useful iron-polyisomaltose
`
`6.
`when prepared by the process of claim l, 2 or ~. or by
`
`an obvious chemical equivalent.
`
`l·'·\
`
`j:z1.
`
`7
`
`. - !
`
`Pharmacosmos, Exh. 1032, p. 7
`
`

`

`SUBSTITUTE
`
`REM PLACEMENT
`
`SECTION is not Present
`
`Cette Section est Absente
`
`Pharmacosmos, Exh. 1032, p. 8
`
`

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